According to a pooled analysis of the GEN501 and SIRIUS studies – the basis for the U.S. Food and Drug Administration’s accelerated approval of daratumumab for patients with previously treated multiple myeloma (MM) – the anti-CD38 monoclonal antibody showed no new safety signals and led to durable responses.

“Daratumumab appears to be a safe and reasonably effective option for patients who are beyond a third line of therapy or have double refractory disease,” Saad Z. Usmani, MD, lead author of the analysis that was published in Blood, told ASH Clinical News.

Dr. Usmani, from the Levine Cancer Institute in Charlotte, North Carolina, and authors analyzed data from both studies, a total of 148 patients with MM who were treated with 16 mg/kg of daratumumab.

The open-label, multi-center, phase I/II, dose-escalation, dose-expansion GEN501 study included MM patients who were relapsed/refractory to two or more previous lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). After a dose-escalation phase, 16 mg/kg of daratumumab was administered once weekly for the first seven doses after the initial dose – which had a three-week washout period – followed by twice monthly for the next eight doses, and monthly thereafter. The primary endpoint was safety, and the secondary endpoint was efficacy.

The open-label, multi-center, phase II SIRIUS study included MM patients who had been treated with three or more lines of therapy, including a PI and IMiD, who were also double-refractory. After an interim analysis, patients received 16 mg/kg of daratumumab once weekly for eight weeks, followed by once every two weeks for the next 16 weeks, and once every four weeks thereafter. The primary endpoint was overall response rate (ORR), and adverse events (AEs) were also monitored.

In the pooled analysis, Dr. Usmani and authors assessed progression-free survival (PFS) and overall survival (OS) in 42 patients from the GEN501 study and 106 from the SIRIUS study.
Within the entire population, patients received a median of five (range = 2-14) prior lines of therapy, with most (76.4%) receiving more than three prior therapies. Most (86.5%) were double-refractory to a PI and an IMiD, with 39.2 percent refractory to carfilzomib and 55.4 percent refractory to pomalidomide. The median treatment duration was 3.4 months (range = 0.03-26 months), and the median number of infusions was 12 (range = 1-40 infusions).

The ORR was 31.1 percent, including 13 very good partial responses, four complete responses, and three stringent complete responses.

“Response achieved by daratumumab-treated patients were rapid (median time to response = 1 month), deep (14% with very good partial response or better), and durable (median duration of response = 7.6 months),” the authors wrote.

After a median follow-up of 20.7 months (range = 0.5-27.1 months), the median PFS was four months (95% CI 2.8-5.6), with 21.6 percent of patients remaining progression-free at 12 months (95% CI 14.4-29.8). The median OS was 20.1 months (95% CI 16.6 – not evaluable); 18- and 24-month OS rates were 56.5 percent (95% CI 47.9-64.2) and 45 percent (95% CI 35.5-54.1), respectively. At 20.7 months, 36 of the 46 patients who responded to daratumumab were still alive. SeeTABLE for a full review of treatment responses.

“The overall response rate of 31 percent suggests that, even though a group of patients clearly benefit from daratumumab as a single agent, perhaps combinations with other drug classes may enhance its activity,” Dr. Usmani said. Of the 107 patients who were eligible for subsequent therapy, 42 (39.2%) responded to the first subsequent therapy with a partial response or better, while 40 (37.4%) had minimal response/stable disease, and 16 (15%) had progressive disease or were not evaluable. The response was unknown for the remaining nine patients (8.4%).

The most common (≥20%) treatment-related adverse events (AEs) included fatigue, nausea, anemia, back pain, cough, upper respiratory tract infection, thrombocytopenia, and neutropenia. Infusion-related reactions occurred in 48 percent of patients, with most occurring during the first infusion (95.8%) and decreasing with subsequent infusions (7%). Most treatment discontinuations were related to progressive disease (83.1%), while 4.1 percent of patients stopped treatment due to AEs. Three deaths occurred that were related to AEs (viral H1N1 infection, pneumonia, and aspiration pneumonia), though the authors determined that these were not related to study treatment.

Dr. Usmani noted that daratumumab is being investigated in a number of ongoing trials, including a phase III study of daratumumab in combination with lenalidomide or bortezomib in relapsed/refractory MM and newly diagnosed MM and a phase I study of daratumumab administered subcutaneously in combination with recombinant human hyaluronidase.

The underlying mechanisms of action that explain daratumumab’s benefits “remain to be elucidated,” the authors wrote, adding that investigators are actively looking at whether daratumumab may enhance a patient’s response to subsequent treatments – including those to which they were previously exposed.